An Expeditious Scalable Synthesis of (S)-2-Amino-5-methoxytetralin via Resolution

Abstract

The first resolution of (±)-2-amino-5-methoxytetralin 1 is achieved via diastereomeric salt formation with (S)-mandelic acid to give (S)-1·HCl of 99.7% ee in 29% overall yield from (±)-1·HCl, (S)-1·HCl being a chiral intermediate to assemble N-0923 2, a potent dopamine D2 agonist effective against Parkinson's disease. Preparation of (±)-1·HCl involves the Birch reduction of 1,6-dimethoxynaphthalene 3b and reductive amination of 5-methoxy-2-tetralone 4 with aqueous NH3 over Raney Ni under a hydrogen atmosphere (2.9−3.9 bar) between 70 and 80 °C. With the off-enantiomer (R)-1 arising from the resolution, its xylene solution is heated at 130 °C over Raney Co under a hydrogen atmosphere (2.0−2.7 bar) to regenerate (±)-1·HCl in 95% yield, which should enhance the overall throughput of the resolution process.